We seek to examine a mechanism-based concept to treat pancreatic adenocarcinoma (PDAC), based on inhibition of the novel immunosuppressive enzyme IDO2, which is specifically activated in PDAC cells. IDO2 has been relatively unexplored compared to the more broadly expressed tryptophan catabolic enzyme indoleamine 2,3-dioxygenase (IDO), which is widely recognized to suppresses T cell activity and mediate immune escape in human cancers. Preclinical studies of IDO inhibitors prompted an NCI immunotherapy workshop to rank them a 'top 10' among experimental agents that could cure cancers. However, as Phase I clinical trials of the lead inhibitor D-1MT have gotten underway, significant questions emerged about the role of IDO in the mechanism of action of the drug. These questions are important since they impede the design of an incisive clinical trial based on mechanistic understanding. In this regard, our proposal addresses a gap in knowledge in the field by redirecting mechanistic focus from IDO to IDO2: in discovering IDO2 we found that it was a preferential biochemical target of D-1MT relative to IDO. Pilot studies suggest that IDO2 activation supports PDAC, implying that D-1MT may offer a therapeutic strategy of particular mechanistic relevance in this disease. Unlike other cancers examined, IDO2 is an active target in human PDAC. Notably, the pattern of naturally occurring genetic variations in the human IDO2 gene which exist in pancreatic cancer patients favor the hypothesis that IDO2 is a driver or facilitator in this disease. Accordingly, our project proposes pharmacological and genetic aims to corroborate the hypothesis that IDO2 blockade could improve PDAC treatment, including in combination with gemcitabine treatment (standard of care). The conceptual, immunological, and genetic innovations offered by our proposal include the use of a unique IDO2-deficient mouse. The work will be conducted by a collaborative multidisciplinary team of leading preclinical and clinical experts in drug discovery and PDAC treatment. The significance and impact of this proposal is based on the powerful opportunity it offers to rationalize and prioritize Phase II clinical trials of D-1MT in pancreatic cancer patients.